Effects of stress and glucocorticoids on CNS oxytocin receptor binding

doi:10.1016/S0306-4530(97)00045-0

Psychoneuroendocrinology

Volume 22, Issue 6, August 1997, Pages 411-422

https://doi.org/10.1016/S0306-4530(97)00045-0 Get rights and content

Abstract

Oxytocin receptors in several regions of the limbic system are regulated by gonadal steroids and play an important role in the mediation of maternal, sexual and affiliative behaviors. We have previously reported oxytocin receptor regulation by glucocorticoids in hippocampus and subiculum-neuroanatomical regions implicated in memory and stress regulation. In the current study we examined oxytocin receptor regulation by stress and high glucocorticoid concentration in adrenally intact male rats. Single prolonged stress and chronic non-habituating stress were used as experimental conditions in the first study, and chronic non-habituating and high dose corticosterone implants in the second. Oxytocin receptor concentration was assessed using in vitro receptor autoradiography with [¹²⁵I]OVTA at the approximate K_D concentration. Both stress paradigms increased oxytocin receptor binding (F = 3.7, df = 2, p = 0.3) across brain regions in the first study. Chronic non-habituating stress and corticosterone implants increased oxytocin receptor binding in the ventral hippocampus only (one-way ANOVA, F = 3.88, df = 2, p < .05). The current studies demonstrate that stress increases oxytocin receptor binding in areas of the CNS that are rich in glucocorticoid receptors, such as hippocampus. This suggests differential regulation of oxytocin receptors in CNS, depending upon their functional role in different regions. Oxytocin receptor modulation could mediate some of the long-term effects of stress on memory, and possibly play a role in the regulation of hypothalamo-pituitary-adrenal stress response. The ability of circulating glucocorticoids to up-regulate these receptors suggests a plausible mechanism for this stress-sensitive regulation.

References (59)

S.M. Antelman et al.
Anticonvulsant and other effects of diazepam grow with time after a single treatment
Pharmacology, Biochemistry and Behavior
(1989)
A. Armario et al.
Effect of a chronic stress model of depression on basal and acute stress levels of LH and Prolactin in adult male rats
Biological Psychiatry
(1988)
E.R. De Kloet et al.
Estradiol induces oxytocin binding sites in rat hypothalamic ventromedial nucleus
European Journal of Pharmacology
(1985)
M. Grassi et al.
Effects of oxytocin on emotional stress and stress-induced gastric lesions
Journal of Physiology, Paris
(1993)
J.P. Herman et al.
Selective forebrain fiber tract lesions implicate ventral hippocampal structures in tonic regulation of paraventricular nucleus corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) mRNA expression
Brain Research
(1992)
T.R. Insel et al.
Central administration of oxytocin modulates the infant rat's response to social isolation
European Journal of Pharmacology
(1991)
T. Ivanyi et al.
Differential effects of emotional and physical stress on the central and peripheral secretion of neurohypophysial hormones in male rats
Life Science
(1991)
D.J. Kennett et al.
Influence of oxytocin on human memory processes: validation by a control study
Life Science
(1982)
G.L. Kovacs et al.
Effect of oxytocin and vasopressin on memory consolidation: sites of action and catecholaminergic correlates after local microinjection into limbic-midbrain structures
Brain Research
(1979)
I. Liberzon et al.
Glucocorticoid regulation of hippocampal oxytocin receptor binding
Brain Research
(1994)

C.A. Lorenzini et al.

Role of dorsal hippocampus in acquisition, consolidation and retrieval of rat's passive avoidance response: a tetrodotoxin functional inactivation study

Brain Research

(1996)

D. Metzger et al.

Facilitation of retention performance in mice by pretest microinjection of AVP into dorsal or ventral hippocampus: differential influence of the peptide on appetitive task

Neuroscience Letters

(1989)

E. Mohr et al.

Functional characterization of estrogen and glucocorticoid responsive elements in the rat oxytocin gene

Brain Research and Molecular Brain Research

(1991)

L.R. Noonan et al.

Neonatal stress transiently alters the development of hippocampal oxytocin receptors

Brain Research and Developments in Brain Research

(1994)

V.K. Patchev et al.

Oxytocin binding sites in rat limbic and hypothalamic structures: site-specific modulation by adrenal and gonadal steroids

Neuroscience

(1993)

L.R. Squire et al.

Memory: brain systems and behavior

Trends in Neuroscience

(1988)

R. Yehuda et al.

Criteria for rationally evaluating animal models of posttraumatic stress disorder

Biological Psychiatry

(1993)

G. Aguilera et al.

Regulation of pituitary vasopressin receptors during chronic stress: relationship to corticotroph responsiveness

Journal of Neuroendocrinology

(1994)

T.L. Bale et al.

Sex differences in and effects of estrogen on oxytocin receptor messenger ribonucleic acid expression in the ventromedial hypothalamus

Endocrinology

(1995)

T.L. Bale et al.

Oxytocin receptor mRNA expression in the ventromedial hypothalamus during the estrous cycle

Journal of Neuroscience

(1995)

C. Barberis et al.

Pharmacology of oxytocin and vasopressin receptors in the central and peripheral nervous system

Annals of the New York Academy of Sciences

(1992)

T.O. Bruhn et al.

Central administration of corticotropin-releasing factor modulates oxytocin secretion in the rat

Endocrinology

(1986)

J.D. Caldwell

Central oxytocin and female sexual behavior

Annals of the New York Academy of Sciences

(1992)

J.D. Caldwell et al.

Thymic oxytocin receptors during development and after steroid treatments in adults

Annals of the New York Academy of Sciences

(1992)

J.D. Caldwell et al.

Effects of steroids and mating on central oxytocin receptors

Annals of the New York Academy of Sciences

(1992)

C.S. Carter et al.

Oxytocin and social bonding

Annals of the New York Academy of Sciences

(1992)

P.B. Chappell et al.

Alterations in corticotropin-releasing factor-like immunoreactivity in discrete rat brain regions after acute and chronic stress

Journal of Neuroscience

(1986)

H. Coirini et al.

Estradiol modulation of oxytocin binding in the ventromedial hypothalamic nucleus of male and female rats

Neuroendocrinology

(1989)

P. Colson et al.

Upregulation of V1a vasopressin receptors by glucocorticoids

American Journal of Physiology

(1992)

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ArticleEffects of stress and glucocorticoids on CNS oxytocin receptor binding

Abstract

Pharmacology, Biochemistry and Behavior

Biological Psychiatry

European Journal of Pharmacology

Journal of Physiology, Paris

Brain Research

European Journal of Pharmacology

Life Science

Life Science

Brain Research

Brain Research

Brain Research

Neuroscience Letters

Brain Research and Molecular Brain Research

Brain Research and Developments in Brain Research

Neuroscience

Trends in Neuroscience

Biological Psychiatry

Regulation of pituitary vasopressin receptors during chronic stress: relationship to corticotroph responsiveness

Journal of Neuroendocrinology

Sex differences in and effects of estrogen on oxytocin receptor messenger ribonucleic acid expression in the ventromedial hypothalamus

Endocrinology

Oxytocin receptor mRNA expression in the ventromedial hypothalamus during the estrous cycle

Journal of Neuroscience

Pharmacology of oxytocin and vasopressin receptors in the central and peripheral nervous system

Annals of the New York Academy of Sciences

Central administration of corticotropin-releasing factor modulates oxytocin secretion in the rat

Endocrinology

Central oxytocin and female sexual behavior

Annals of the New York Academy of Sciences

Thymic oxytocin receptors during development and after steroid treatments in adults

Annals of the New York Academy of Sciences

Effects of steroids and mating on central oxytocin receptors

Annals of the New York Academy of Sciences

Oxytocin and social bonding

Annals of the New York Academy of Sciences

Alterations in corticotropin-releasing factor-like immunoreactivity in discrete rat brain regions after acute and chronic stress

Journal of Neuroscience

Estradiol modulation of oxytocin binding in the ventromedial hypothalamic nucleus of male and female rats

Neuroendocrinology

Upregulation of V1a vasopressin receptors by glucocorticoids

American Journal of Physiology

Article
Effects of stress and glucocorticoids on CNS oxytocin receptor binding